p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev, Vladimir A.; Flores, Elsa R.

doi:10.1101/cshperspect.a015248

Cited by 97 publications

(96 citation statements)

References 88 publications

(124 reference statements)

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“…Both TAp63 and DNp63 are important for skin and epidermal development (reviewed by (Botchkarev and Flores, 2014). Transgenic KO mice for p63 die at birth.…”

Section: P63 and Skin Developmentmentioning

confidence: 99%

P63 in health and cancer

Gonfloni

Caputo²,

Iannizzotto³

2015

Int. J. Dev. Biol.

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TP63 is the most ancient member of the p53 gene family. The p53 family comprises three transcription factors (p53/p63/p73). They share a high degree of homology and similar domain structure. Yet, they can exist as truncated isoforms. Alternative promoters and splicing sites lead to the generation of several molecules. P53/p63/p73 are important to maintain cell homeostasis. P63 and p73 regulate many p53 target genes. This is due to their common structural features. Both proteins may compensate the loss of p53. This is a common event occurring in more than 50% of malignancies. Yet, p63 (or p73) has its own role. Studies from p63-null mice have shown the key role of p63 in embryo development. Several reports have supported the p63 role in epidermal development and in skin homeostasis. P63 involvement in heart development is currently being researched. Recent studies have found p63 to be "the guardian of human reproduction". In addition, p63 has an important, even controversial, role in cancer. Here, we provide a general overview of p63 regulation and activity. We discuss emerging concepts about its role in germ line protection, metabolism and cancer.

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“…Both TAp63 and DNp63 are important for skin and epidermal development (reviewed by (Botchkarev and Flores, 2014). Transgenic KO mice for p63 die at birth.…”

Section: P63 and Skin Developmentmentioning

confidence: 99%

P63 in health and cancer

Gonfloni

Caputo²,

Iannizzotto³

2015

Int. J. Dev. Biol.

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“…The expression patterns of Foxa1, regulating sweat secretion; Nkcc1, the major player in the NKCC cotransporter model; and p63, a master regulator of keratinocyte differentiation and proliferation (Botchkarev and Flores, 2014; Cui and Schlessinger, 2015) were also analyzed for expression patterns and found to be unchanged in the cKO mice (Fig. S2c, d).…”

Section: Resultsmentioning

confidence: 99%

Foxc1 Ablated Mice Are Anhidrotic and Recapitulate Features of Human Miliaria Sweat Retention Disorder

Cui

Ishii

Campbell

et al. 2017

Journal of Investigative Dermatology

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Sweat glands are critical for thermoregulation. The single tubular structure of sweat glands has a lower secretory portion and an upper reabsorptive duct leading to the secretory pore in the skin. Genes that determine sweat gland structure and function are largely unidentified. Here we report that a Fox family transcription factor, Foxc1, is obligate for appreciable sweat duct activity in mice. When Foxc1 was specifically ablated in skin, sweat glands appeared mature, but the mice were severely hypohidrotic. Morphological analysis revealed that sweat ducts were blocked by hyperkeratotic or parakeratotic plugs. Consequently, lumens in ducts and secretory portions were dilated, and blisters and papules formed on the skin surface in the knockout mice. The phenotype was strikingly similar to the human sweat retention disorder miliaria. We further show that Foxc1 deficiency ectopically induces the expression of keratinocyte terminal differentiation markers in the duct luminal cells, which most likely contribute to keratotic plug formation. Among those differentiation markers, we show that Sprr2a transcription is directly repressed by over-expressed Foxc1 in keratinocytes. In summary, Foxc1 regulates sweat duct luminal cell differentiation, and mutant mice mimic miliaria and provide a possible animal model for its study.

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“…The p63 transcription factor operates as master regulator of this program, and subsequently and stage-dependently induces in the epidermal progenitor cells expression of several groups of genes encoding the essential components of the cytoskeleton (keratins 5 and 14), cell adhesion molecules (P-cadherin, integrin-α3, Perp, dystonin, and so on), cell matrix regulators (Fras-1), transcription factors (AP-2γ, IKKα, IRF6), and epigenetic regulators (Satb1, Brg1) involved in the control of epidermal differentiation (Koster and Roop, 2007; Vanbokhoven et al ., 2011; Botchkarev and Flores, 2014). …”

Section: Molecular Control Of Cell Differentiationmentioning

confidence: 99%

“…p63 has multiple isoforms, including TAp63 and ΔNp63, which show distinct, although partially overlapping, roles in the control of epidermal differentiation and stratification (Koster and Roop, 2007; Vanbokhoven et al ., 2011; Botchkarev and Flores, 2014). The ΔNp63 isoform is more abundant in the epidermis compared with TAp63, is strongly expressed in basal epidermal KCs, and is markedly downregulated in the spinous layer (Romano et al ., 2012).…”

Section: Molecular Control Of Cell Differentiationmentioning

confidence: 99%

Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation

Botchkarev

2015

Journal of Investigative Dermatology Symposium Proceedings

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The epidermal differentiation program is regulated at several levels including signaling pathways, lineage-specific transcription factors, and epigenetic regulators that establish well-coordinated process of terminal differentiation resulting in formation of the epidermal barrier. The epigenetic regulatory machinery operates at several levels including modulation of covalent DNA/histone modifications, as well as through higher-order chromatin remodeling to establish long-range topological interactions between the genes and their enhancer elements. Epigenetic regulators exhibit both activating and repressive effects on chromatin in keratinocytes (KCs): whereas some of them promote terminal differentiation, the others stimulate proliferation of progenitor cells, as well as inhibit premature activation of terminal differentiation-associated genes. Transcription factor-regulated and epigenetic mechanisms are highly connected, and the p63 transcription factor has an important role in the higher-order chromatin remodeling of the KC-specific gene loci via direct control of the genome organizer Satb1 and ATP-dependent chromatin remodeler Brg1. However, additional efforts are required to fully understand the complexity of interactions between distinct transcription factors and epigenetic regulators in the control of KC differentiation. Further understanding of these interactions and their alterations in different pathological skin conditions will help to progress toward the development of novel approaches for the treatment of skin disorders by targeting epigenetic regulators and modulating chromatin organization in KCs.

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p53/p63/p73 in the Epidermis in Health and Disease

Cited by 97 publications

References 88 publications

P63 in health and cancer

P63 in health and cancer

Foxc1 Ablated Mice Are Anhidrotic and Recapitulate Features of Human Miliaria Sweat Retention Disorder

Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation

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